Oral pharmaceutical forms of liquid drugs having improved bioavailability

ABSTRACT

The present invention relates to new pharmaceutical compositions for the administration of liquid drugs in solid oral forms, said compositions comprising one or more active ingredients, one or more surface-active agents and optionally a co-surfactant and/or an absorption enhancer absorbed on a solid inert carrier.

The present invention relates to new pharmaceutical compositions for theadministration of liquid drugs in solid oral forms, said compositionscomprising one or more active ingredients, one or more surface-activeagents and optionally a co-surfactant and/or an absorption enhancerabsorbed on a solid inert carrier.

It is well known in the art that it is difficult to orally administerdrugs, which are liquid at room temperature. Generally, these drugs showa poor water solubility and therefore a limited absorption, resulting ina poor bioavailability together with an absorption characterized by astrong inter- and intra-subject variability. Therefore, it would beimportant to have at disposal compositions able to improve thesecharacteristics that could seriously compromise the bioavailability aswell as the therapeutic activity of said compounds.

Generally, oily drugs are formulated in soft or hard gelatine capsuleswhich present technical problems relating to filling, losses etc. Theycan be also absorbed on inert carriers, but in this case even though thetechnological problems can be solved, it is impossible to improve thebioavailability.

In WO 01/66087 and WO 01/66088 pharmaceutical compositions for oraladministration of a liquid active ingredient, for example anitrooxyderivative of naproxen or other NSAIDs, are disclosed. Saidcompositions comprise, further to the active ingredient, one or moresurfactants, optionally an oily or semi-solid fat or one or moreshort-chain alcohols. These compositions form an oil-in-water emulsionin situ upon contact with aqueous media such as gastrointestinal fluids.

In WO 95/08983 a self-emulsifying composition suitable for oraladministration is disclosed, said composition forming a microemulsion insitu upon contact with biological fluids. The described compositioncomprises an active ingredient, a lipophilic phase consisting of amixture of glycerides and fatty acids esters, a surface-active agent, aco-surfactant and a hydrophilic phase consisting of the gastrointestinalfluids.

In EP 274 870 a pharmaceutical composition containing a non-steroidalanti-inflammatory drug (NSAID) and a surfactant is described, saidcomposition being able to form micelles containing said activeingredient upon oral administration

In WO 01/41737 an immediate-release solid oral pharmaceuticalcomposition, comprising a solid carrier and a liquid drug or a solutionof a poor soluble drug, is described.

It has been now surprisingly found that it is possible to improve theoral bioavailability of liquid drugs at room temperature, by formulatingthe solid drug in solid pharmaceutical compositions able to formemulsions in situ upon contact with the biological fluids and with thewater used for ingesting the pharmaceutical form.

In particular, the present invention relates to the preparation of solidpharmaceutical compositions for oral administration consisting of anadmixture absorbed in a solid inert carrier, said admixture comprising:

i) one or more liquid active ingredients and

ii) one or more surfactants and

iii) optionally a co-surfactant and/or

iv) optionally an absorption enhancer

said composition forming an oil-in-water emulsion upon contact withaqueous media such as biological fluids. Particularly preferred is apharmaceutical composition according to claim 1 wherein the admixtureabsorbed in the inert carrier comprises:

-   -   i) one or more liquid active ingredients;    -   ii) one or more surfactants;    -   iii) an absorption enhancer

For liquid active ingredient, a drug being liquid, generally oily, atroom temperature is meant. Examples of drugs being oily liquids at roomtemperature are for example several nitrate esters of drugs such as thenon-steroidal anti-inflammatory drugs (NSAIDs) described in EP 609415,EP 670825, EP 722434, EP 759899 and patent applications WO 00/51988, WO00/61537, WO 00/61541 e WO 01/54691 in the name of applicant.

Examples of said nitrate esters are the following:

(S)-3-benzoyl-α-methylbenzeneacetic acid 3-(nitrooxy)propyl ester

(S)-3-benzoyl-α-methylbenzeneacetic acid 4-(nitrooxymethyl)phenyl-methylester

2-[(2,6-dichlorophenyl)amino]benzeneacetic acid5-(nitrooxy)ethyl-oxyethyl ester

2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(nitrooxy)butyl ester(NO-Diclofenac)

2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid 3-(nitrooxy)propylester

2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 6-(nitrooxy)hexyl ester

3-benzoyl-α-methylbenzeneacetic acid 4-(nitrooxy)butyl ester

3-benzoyl-α-methylbenzeneacetic acid 6-(nitrooxy)hexyl ester

3-benzoyl-α-methylbenzeneacetic acid 5-(nitrooxy)ethyloxyethyl ester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid 3-(nitrooxy)propylester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid 4-(nitrooxy)butylester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid 6-(nitrooxy)hexylester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid5-(nitrooxy)ethyl-oxyethyl ester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid4-(nitrooxymethyl)-phenylmethyl ester

(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid 6-(nitrooxy)hexyl ester

(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid5-(nitrooxy)ethyl-oxyethyl ester

(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid 4-nitrooxy-2-butenylester

trans-3-[4-[α-methyl-4-(2-methylpropyl)benzene]acetyloxy]-3-methoxy-phenyl]-2-propenoicacid 4-(nitrooxy)butyl ester

2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetic acid 4-(nitrooxy)butyl ester(NO-Flurbiprofen)

(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid 4-(nitrooxy)butyl ester(NO-Naproxen)

2-(acetyloxy)benzoic acid 4-(nitrooxy)butyl ester

2-(acetyloxy)benzoic acid 5-(nitrooxy)ethyloxyethyl ester

3-(6-methoxy-α-methyl-2-naphthaleneacetyl)-thiazolidine-4-carboxylicacid 4-(nitrooxy)-butyl ester

N-(2-nitrooxyethyl)-2-fluoro-α-methyl[1,1′-biphenyl]-4-acetamide

3-[2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetyl]-thiazolidine-4-carboxylicacid 4-(nitrooxy)butyl ester

α-methyl-4-(2-methylpropyl)benzeneacetic acid 6-(nitrooxy)hexyl ester

α-methyl-4-(2-methylpropyl)benzeneacetic acid 3-(nitrooxy)propyl ester

(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid1-nitrooxy-2-methyl-2-propyl ester

(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid 10-(nitrooxy)decyl ester

α-methyl-4-[(2-oxocyclopentyl)methyl]benzeneacetic acid4-(nitrooxy)-butyl ester

3-(6-methoxy-α-methyl-2-naphthaleneacetyl)-R(−)-2-oxothiazolidine-4-carboxylicacid 4-(nitrooxy)butyl ester

(S)-N-acetyl-[α-methyl-4-(2-methylpropyl)benzene-acetyl]-cysteine4-(nitrooxy)butyl ester

2-[2,6-dichlorophenyl)amino]benzeneacetic acid 2-(nitrooxy)ethyl ester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid4-(nitrooxy-methyl)phenylmethyl ester

(S)-N-acetyl-[2-fluoro-α-methyl(1,1′-biphenyl)-4-acetyl]cysteine4-(nitrooxy)butyl ester

α-methyl-4-(2-methylpropyl)benzeneacetic acid 4-(nitrooxy)butyl ester

trans-3-[4-[2-fluoro-α-methyl(1,1′-biphenyl)-4-acetyloxy]-3-methoxy-phenyl]-2-propenoicacid 4-(nitrooxy)butyl ester

(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid4-(nitrooxy)-4-methylbutyl ester

2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetic acid 3-(nitrooxymethyl)phenylester

2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetic acid6-(nitrooxymethyl)-2-methylpyridyl ester

2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)-methylphenyl ester

2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetic acid 3-(nitrooxy)propyl ester

4-(nitrooxy)butanoic acid 2-methyl-5-nitroimidazole-1-ethyl ester

1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid 4-(nitrooxy)butyl ester

Norfloxacine 4-(nitrooxy)butyl ester

Further examples of liquid drugs are nicotine, nitroglycerin, valproicacid, benzonatate, clofibrate, clorfeniramine, clorfenoxamine,clorfentermine and clorpromazine and liquid vitamins.

The compositions of the invention are able to form an emulsion, uponingestion of the pharmaceutical form by a patient, having reduceddroplet size. The average droplet size of the emulsion is of from 0.1and 50 microns and preferably is less than 5 micron.

The emulsion droplet size is measured by simulating the formation of anemulsion by adding in a beaker 50 ml of a 0.1N HCl aqueous solution and100 mg of the composition under examination. The time required for themixture to form an emulsion, can vary from 20 seconds to 10 minutesdepending on the composition. The average droplet size of the emulsionwas then determined by employing the light scattering technique orelectronic microscopy.

Examples of surfactants that can be employed are anionic, non-ionic andcationic surfactants. Examples thereof may include, but are not limitedto, alkaline soaps, such as sodium and potassium stearate, organicamines soaps, sulphuric esters, such as sodium lauryl sulphate,monolauryl glycerosulphuric acid sodium salt, alkyl aryl sulfonates,esters and ethers of polyethylene glycols, polysorbates, benzalkoniumchloride, cetyltrimethylammonium bromide, cetrimide, particularly thecommercially available products Arlacel, Tween, Capmul, Cremophor,Labrafac, Labrafil, Labrasol, etc. In a few cases it can be useful toadd also co-surfactants, that is when a well definite HLB(hydrophilic-lipophilic balance) is requested. Preferred co-surfactantsare straight or branched chain alcohols, preferably C₁-C₆ alcohols, suchas ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol,isobutyl alcohol, and polyols such as glycerol, ethylene glycol,propylene glycol, isopropylene glycol, butylene glycol, isobutyleneglycol.

In order to improve the absorption, an absorption enhancer can be addedto the active ingredient, dissolved or suspended in the surface-activeagent and optionally in the co-surfactant. Many substances possess saidactivity and among these the following can be mentioned: polysorbates,sorbitan esters, sodium dioctyl sulfosuccinate, ethoxydiglycol,ethoxylated nonyl phenols, polyethylene lauryl ether, phospholipidderivatives, fatty acid esters, biliary acid derivatives, aproticsolvents such as dimethyl sulfoxide, dimethylformamide,dimethylacetamide and 2-pyrrolidone.

The active ingredient, surfactants and absorption enhancer admixture isallowed to absorb on an inert carrier in such a ratio to obtain a powderhaving good technological characteristics as far as for examplefree-flowing is concerned. For the absorption of said mixture generallygranulators, kneaders or mixers normally used in the pharmaceuticalfield can be employed. Generally the mixture/solid carrier ratio mayvary from 1:20 to 10:1 even though the preferred ratio is from 1:2 to2:1.

As solid carrier any non toxic pharmaceutical compound may be used,including for example clays such as bentonite, kaolin, silicaderivatives such as Aerosil, Cabosil, cellulose derivatives such asAvicel, silicates such as magnesium trisilicate, talc, hydroxides suchas magnesium and aluminium hydroxide, starches, sugars andcyclodextrins. Silica is the preferred absorber.

The ratio by weight of active ingredient: surfactant may vary from 1:0.1to 1:10, preferably of from 1:0.3 to 1:3.

The ratio by weight of co-surfactant:surfactant may vary from 1:0.1 to1:5, preferably of from 1:0.1 to 1:5.

The ratio by weight of absorption enhancer:surfactant may vary from1:0.1 to 1:10, preferably of from 1:0.3 to 1:3.

The ratio by weight of admixture : solid carrier may vary from 1:20 to10:1, preferably of from 1:2 to 2:1.

The resulting product is a free-flowing powder that can be employed inseveral pharmaceutical forms in the form for example of sachet), tablets(chewing, effervescent or quick dissolution tablets), controlled releasecapsules or tablets so as to have the active ingredient release inparticular areas of the gastrointestinal tract; for this purpose, thecoating will be gastroresistant or specifically directed into gut areas,for example colon.

Depending on the pharmaceutical form type, it is possible to usesuitable excipients for having the desired formulation. Thus in the caseof sachets, sugars, suspending agents, flavourings and sweeteners can beemployed, whereas for tablets and capsules, diluents, disintegrants andlubricants can be used. Examples for these materials can be found inRemington's Pharmaceutical Sciences, 17th Edition, Mack PublishingCompany, Easton, Pa., 1985.

EXAMPLES Example 1

Preparation of 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid4-(nitrooxy)butyl ester (NO-diclofenac; formula (IV)) absobed oncolloidal silica Compound of formula (IV) 100 g Cremophor EL  50 gPhospholipon 80 H  50 g Aerosil 200 100 g Explotab 100 g

Cremophor EL and compound of formula IV were added in a suitable vesseland mixed to homogeneity. In the same time Aerosil 200, Phospfolipon 80H and Explotab were mixed separately. The powder mixture was slowlyintroduced in a mixer under stirring until complete absorption of thecomponents was achieved. Emulsion average droplet size: 2.2 micron(minimum 0.27, maximum 13.3).

Example 2

Preparation of a pharmaceutical powder form (sachet) for oral useemploying the active ingredient mixture of Example 1 Mixture of Example1 400 g Orange aroma powder 150 g Lemmon aroma  50 g Saccharin sodium 10 g Saccharose 2390 g 

For preparing sachets, NO-diclofenac absorbed as described in Example 1was mixed adding orange and lemon flavour as well as saccharin sodiumand saccharose. A cube mixer was used with stirring at 9 rpm for 15minutes. The mixture was distributed in sachets each weighing 3.0 g.

Dissolution Test

On the mixture obtained as described in Example 2, a dissolution testwas carried out in 0.1N HCl at 37° C. with a rotation speed of 50 rpm.The dissolution results are listed in Table 1. TABLE 1 NO-diclofenacabsorbed on Aerosil 200 (without Composition of the invention forming anemulsion) (example 2) Time % dissolved % dissolved 0 0 0 15 3.4 88.7 304.8 90.2 60 5.7 93.2

Example 3

Preparation of 2-fluoro-α-methyl(1,1′-biphenyl)-4-acetic acid4-(nitrooxy)butyl ester (NO-flurbiprofen; formula (XIX)) absorbed oncolloidal silica NO-flurbiprofen 406 g Cremophor EL 106 g Aerosil 200300 g Explotab 200 g

A suitable vessel was charged with NO-flurbiprofen and Cremophor EL andthe mixture was stirred until a homogenous product was obtained.Separately, Aerosil 200 was mixed with Explotab and the whole was addedto the previous mixture to give a homogenous mixture that was poured ona 0.85 mm sieve.

Average emulsion droplet size: 1.5 micron (minimum 0.20; maximum 12.8).

Example 3.1

Preparation of a pharmaceutical powder form for oral use (sachets)employing the active ingredient mixture obtained in example 3 Mixture ofexample 3 1000 g Saccharin sodium 20 g Orange aroma 300 g Saccharose4674 g

For preparing 3 g sachets, each containing 200 mg of active ingredient,1000 g of the mixture obtained as previously described in example 3 weremixed with saccharin sodium, orange aroma and saccharose.

Example 3.2

Preparation of tablets employing the mixture of example 3. Mixture ofexample 3 500 g PVP K30 20 g Avicel pH 102 277 g

PVP K 30 was dissolved in 300 g water and the solution was used to wetthe mixture of example 3 in a Erweka mixer. The product thus obtainedwas poured on a 2 mm sieve and then it was dried in an oven at 40° C.for 3 hours. Afterwards, it was poured on a 1 mm sieve in a floatinggranulator and Avicel was added under stirring in a V mixer for 15minutes. The product was compressed to the theoretical weight of 800 mgwith a 18×10 mm oblong punch. Tablets having the followingcharacteristics were obtained:

-   Title of a.i. NO-flurbiprofen: 201.3 mg/cpr-   Hardness: 4 Kp-   Friability: <0.1%-   Disgregation time: 4 min

Example 4

Preparation of a solid pharmaceutical form (granulate) using(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid 4-(nitrooxy)butyl ester(NO-Naproxen; compound of formula (XX)) NO-Naproxen 100 mg Tween 80 50mg Phospholipon 80 H 50 mg Aerosil 200 100 mg Explotab 100 mg

100 mg of Phospholipon 80 H were dispersed in 2.5 ml water by heating at85° C. The dispersion of Phospholipon 80 H was added under stirring to amixture of NO-Naproxen and Tween 80. After adding Phospholipon, Aerosiland Explotab were added under stirring. A granulate was obtained anddried in an oven. The granulate was sieved through a 600 μm sieve. Bydispersing 400 mg of this granulate in 20 ml water, an emulsion havingan average droplet size of 2.2 micron was obtained (minimum 0.27;maximum 13.3).

Example 5

Preparation of coated tablets employing the tablets obtained asdescribed in example 3.2 NO-Flurbiprofen tablets of ex. 3.2 800 gMethocel E15 150 g Titanium dioxide 20 g Talc 20 g PEG 600 30 g 96%alcohol 1600 g

Methocel E 15 and PEG 6000 were dissolved in a suitable vessel and thentalc and titanium dioxide were dispersed therein. The tablets preparedas described in example 3.2 were charged in a Pellegrini vessel and thetablet coating was performed with the film forming suspension accordingto the following parameters:

-   Air entry: 60° C. (300 mc³/h)-   Suction: 0.4 mc³/h-   Drum rotation: 4 r/m-   Film forming solution range: 30 ml/min

Example 6

Preparation of gastroresistant coated tablets employing the tabletsobtained as described in example 3.2 Tablets prepared according toexample 3.2 19 kg Eudragit E 30 D 0.49 kg Talc 0.19 kg Triethyl citrate0.05 kg Titaniun dioxide 0.05 kg Silicon antifoam 0.005 kg

Eudragit L30D was poured in 1.1 kg water under stirring to avoidfoaming. 6.5 g NaOH were added and stirring was continued for further 30minutes. A latex was obtained that was sieved through a 0.25 mm meshsieve. Triethyl citrate, talc and antifoam agent were added, then thesuspension was homogenized together with the Eudragit suspension. Thetablets prepared according to example 3.2 were introduced into a vesseland sprayed with the mixture obtained as mentioned above, by employing aperistaltic pump and a Graco atomizer gun. The mixture was sprayed witha pressure of 1.5 bar and at a rate of 40 g/minute with an air capacityof 7 m³/minute at 55° C. The tablets temperature was maintained at 34°C.

Example 7

In man evaluation of pharmacokinetic and pharmacodynamic parameters ofthe oral NO-diclofenac formulation described in example 2 (sachets).

Six healthy fastened patients were administered with 75, 100 and 150 mgNO-Diclofenac sachets formulated as described in example 2.

In order to evaluate the pharmacokinetic parameters, blood samples weretaken at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 32 hoursafter administration of the pharmaceutical formulation. The activeingredient NO-diclofenac and its metabolites diclofenac and thehydroxyderivative 4-OH-diclofenac were dosed in plasma by a LC/MS/MSmethod, previously validated. NO-diclofenac was not found in the samplesat any dosage. The pharmacokinetic parameters of plasma levels obtainedfor diclofenac (D) and the 4-hydroxydiclofenac (40H-Diclofenac, 40H-D)are reported in Table 2.

The inhibition of COX-1/COX-2, in blood samples taken at 0.5, 1, 3, 6,10, 24 and 32 hours after administration, was also evaluated in the samepatients. The obtained results are listed in Table 3. TABLE 2 Sachets100 mg D 4OH-D C_(max) (ng/mL) 415.7 281 T_(max) (h) 0.55 1.4 t½ (h)6.85 11.3 AUC_((0-t)) 1097.1 2446.2 AUC_((0-∞)) 1168.5 2909.0 MRT (h)7.31 16.1

TABLE 3 COX 1 and COX 2 inhibition Predose 1 h 10 h % % % ng/mlInhibition ng/ml Inhibition ng/ml Inhibition COX 1 24.95 0 5.28 −60%14.03 −19% (TBX2) COX 2 55.29 0 29.55 −75% 10.55 −108%  (PGE2)

The results obtained both as pharmacokinetics and as pharmacodynamicsconfirm that the NO-diclofenac formulation described in example 2 has agood bioavailability in terms of plasmatic levels of diclofenac and ofanti-inflammatory activity measured according to the ciclooxygenase 1and 2 inhibition.

Example 8

Comparison of NO-flurbiprofen bioavailability (Formula XIX) formulatedin usual gelatine capsules vs sachets and tablets.

8.1 : Pharmaceutical forms

8.1.A) Usual tablets NO-flurbiprofen 100 mg Mais starch 300 mg Avicel 40mg Talc 20 mg Colloidal silica 5 mg Carboxymethylcellulose 40 mgMagnesium stearate 10 mg

The active ingredient was absorbed on starch and silica withoutsurfactants and absorption enhancers. After absorption, the granulatewas mixed with talc, magnesium stearate and carboxymethylcellulose andfilled in hard gelatine capsules.

8.1.B) Sachets

Sachets have been prepared as described in example 3.1

8.1.C) Tablets

Tablets have been prepared as described in example 3.2

The bioavailability study has been performed on 12 healthy subjects. Thesubjects were administered each at three different times and in arandomized way with two 100 mg capsules, 200 mg caps and 200 mg tabletscontaining each NO-flurbiprofen.

Blood samples were taken after each administration at the here belowlisted times: 0.25, 0.50, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours.Flurbiprofen concentration in every plasmatic sample was determined by aLC/MS/MS method.

The obtained results are reported in FIG. 1, and the pharmacokineticparameters are presented in Table 4.

The obtained results show that both sachets and tablets arenon-bioequivalent in comparison with usual capsules, as they give abetter absorption both in terms of C_(max) and in terms of AUC. TABLE 4Formulation Formulation Formulation 8.1.A 8.1. B 8.1.C (2 × 100 mg (200mg (200 mg capsules) sachets ) tablets) C_(max) (μg/mL) 5.8 9.7 9.2T_(max) (h) 3 3 3 t½ (h) 21.2 8.7 10.2 AUC_((0-t)) 62.7 86.3 83.2

1. A pharmaceutical composition for oral administration consisting of anadmixture absorbed in a solid inert carrier, said admixture comprising:i) one or more liquid active ingredients and ii) one or more surfactantsand iii) optionally a co-surfactant and/or optionally an absorptionenhancer said composition forming an oil-in-water emulsion upon contactwith aqueous media such as biological fluids.
 2. A pharmaceuticalcomposition according to claim 1 wherein the admixture absorbed in theinert carrier comprises: one or more liquid active ingredients; one ormore surfactants; an absorption enhancer
 3. A pharmaceutical compositionaccording to claim 1 wherein said composition forms an oil-in-wateremulsion with an average droplet size of from 0.05 micron to 50 micronupon contact with aqueous media such as biological fluids.
 4. Apharmaceutical composition according to claim 1 wherein said compositionforms an oil-in-water emulsion with an average droplet size of less than5 micron upon contact with aqueous media such as biological fluids.
 5. Apharmaceutical composition according to claim 1 wherein the liquidactive ingredient is a NO-releasing non-steroidal anti-inflammatorydrug.
 6. A pharmaceutical composition according to claim 3, wherein theNO-releasing non-steroidal anti-inflammatory drug is selected from thegroup consisting of: (S)-3-benzoyl-α-methylbenzeneacetic acid3-(nitrooxy)propyl ester

(S)-3-benzoyl-α-methylbenzeneacetic acid 4-(nitrooxymethyl)-phenylmethylester

2-[(2,6-dichlorophenyl)amino]benzeneacetic acid5-(nitrooxy)ethyl-oxyethyl ester

2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4(nitrooxy)butyl ester(NO-Diclofenac)

2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid 3-(nitrooxy)propylester

2-[(2,6-dichlorophenl)amino]benzeneacetic acid 6-(nitrooxy)hexyl ester

3-benzoyl-α-methylbenzeneacetic acid 4-(nitrooxy)butyl ester

3-benzoyl-α-methylbenzeneacetic acid 6-(nitrooxy)hexyl ester

3-benzoyl-α-methylbenzeneacetic acid 5-(nitrooxy)ethyloxyethyl ester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid 3-(nitrooxy)propylester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid 4-(nitrooxy)butylester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid 6-(nitrooxy)hexylester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid5-(nitrooxy)-ethyloxyethyl ester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid4-(nitrooxymethyl)-phenylmethyl ester

(S)-6-methoxy-α-methyl-2-naphtaleneacetic acid 6-(nitroxy)hexyl ester

(S)-6-methoxy-α-methyl-2-naphtaleneacetic acid5-(nitrooxy)ethyl-oxyethyl ester

(S)-6-methoxy-α-methyl-2-naphtaleneacetic acid 4-nitrooxy-2-butenylester

trans-3-[4-[α-methyl-4-(2-methylpropyl)benzene]acetyloxy]-3-methoxy-phenyl]-2-propenoicacid 4-(nitrooxy)butyl ester

2-fluoro-α-methyl[1,1′-biphenyl]-4-acetic acid 4-(nitrooxy)butyl ester(NO-Flurbiprofen)

(S)-6-methoxy-α-methyl-2-naphtaleneacetic acid 4-(nitrooxy)butyl ester(NO-Naproxen)

2-(acetyloxy)benzoic acid 4-(nitrooxy)butyl ester

2-(acetyloxy)benzoic acid 5-(nitrooxy)ethyloxyethyl ester

3-(6-methoxy-α-methyl-2-naphtalenacetyl)-thiazolidin-4-carboxylic acid4-(nitrooxy)butyl ester

N-(2-nitrooxyethyl)-2-fluoro-α-methyl[1,1′-biphenyl]-4-acetamide

3-[2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetyl]-thiazolidin-4-carboxylicacid 4-(nitrooxy)butyl ester

α-methyl-4-(2-methylpropyl)benzeneacetic acid 6-(nitrooxy)hexyl ester

α-methyl-4-(2-methylpropyl)benzeneacetic acid 3-(nitrooxy)propyl ester

(S)-6-methoxy-α-methyl-2-naptaleneacetic acid1-nitrooxy-2-metyl-2-propyl ester

(S)-6-methoxy-α-methyl-2-naphtaleneacetic acid 10-(nitrooxy)decyl ester

α-methyl-4-[(2-oxocyclopentyl)methyl]benzeneacetic acid4-(nitrooxy)butyl ester

3-(6-methoxy-α-methyl-2-naphtalenacetyl)-R(−)-2-oxothiazolidin-4-carboxylicacid 4-(nitrooxy)butyl ester

(S)-N-acetyl-[α-methyl-4-(2-methylpropyl)benzeneacetyl]-cysteine4-(nitrooxy)butyl ester

2-[2,6-dichlorophenyl)amino]benzeneacetic acid 2-(nitrooxy)etyl ester

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid4-(nitrooxymethyl)-phenylmethyl ester

(S)-N-acetyl-[2-fluoro-α-methyl(1,1′-biphenyl)-4-acetyl]cysteine4-(nitrooxy)butyl ester

α-methyl-4-(2-methylpropyl)benzeneacetic acid 4-(nitrooxy)butyl ester

trans-3-[4-[2-fluoro-α-metyl(1,1′-biphenyl)-4-acetyloxy]-3-methoxy-phenyl]-2-propenoicacid 4-(nitrooxy)butyl ester

(S)-6-methoxy-α-methyl-2-naphtaleneacetic acid4-(nitrooxy)-4-methylbutyl ester

2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetic acid 3-(nitrooxymethyl)phenylester

2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetic acid6-(nitrooxymethyl)-2-methylpyridyl ester

2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)-methylphenyl ester

2-fluoro-α-methyl[1,1′-biphenyl]-4-acetic acid 3-(nitrooxy)propyl ester

4-(nitrooxy)butanoic acid 2-methyl-5-nitroimidazole-1-ethyl ester

1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid 4-(nitrooxy)butyl ester

Norfloxacine 4-(nitrooxy)butyl ester


7. A pharmaceutical composition according to claim 1, wherein the liquidactive ingredient is selected from the group consisting of nicotine,nitroglycerin, valproic acid, benzonatate, clofibrate, clorfeniramine,clorfenoxamine, clorfentermina and clorpromazine, liquid vitamins andmixtures thereof.
 8. A pharmaceutical composition according to claim 1,wherein the surfactant is selected from cationic, anionic and non ionicsurfactant such as alkaline soaps, organic amines soaps, sulphuricesters, alkyl aryl sulfonate, polyethylene glycol esters and ethers,polysorbates.
 9. A pharmaceutical composition according to claim 8wherein the surfactant is selected from the group consisting of sodiumstearate, potassium stearate, sodium lauryl sulfate, sodium monolaurylglycerosulfate, benzalkonium chloride, cetyltrimethylammonium bromide,cetrimide, Arlacel, Tween, Capmul, Cremophor, Labrafac, Labrafil andLabrasol or mixtures thereof.
 10. A pharmaceutical composition accordingto claim 1, wherein the co-surfactant is selected from straight orbranched chain alcohols, preferably C₁-C₆ alcohols, such as ethylalcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutylalcohol, and polyols such as glycerol, ethylene glycol, propyleneglycol, isopropylene glycol, butylene glycol, isobutylene glycol.
 11. Apharmaceutical composition according to claim 1, wherein the absorptionenhancer is selected from polysorbates, sorbitan esters, dioctyl sodiumsulfosuccinate, ethoxy diglycol, ethoxylated nonyl phenols, polyethylenelaurylether, phospholipid derivatives, fatty acids esters, biliary acidsderivatives, aprotic solvents such as dimethyl sulfoxide,dimethylformamide, dimethylacetamide and 2-pyrrolidone.
 12. Apharmaceutical composition according to claim 1, wherein the inert solidcarrier is selected from the group consisting of clays such bentonite,kaolin, silica derivatives such as Aerosil, Carbosil, cellulosederivatives such as Avicel, silicates such as magnesium trisilicate,talc, earth-alkaline metal hydroxides such as magnesium and aluminiumhydroxide, starch, sugars and cyclodextrines.
 13. A pharmaceuticalcomposition according to claim 9 wherein the inert solid carrier issilica.
 14. A pharmaceutical composition according to claim 1, whereinthe ratio of active ingredient:surfactant is of from 1:0.1 to 1:10. 15.A pharmaceutical composition according to claim 1, wherein the ratio ofco-surfactant:surfactant is of from 1:0.1 to 1:5.
 16. A pharmaceuticalcomposition according to claim 1, wherein the ratio of absorptionenhancer:surfactant is of from 1:0.1 to 1:10.
 17. A pharmaceuticalcomposition according to claim 1, wherein the ratio of admixture:solidcarrier is of from 1:20 to 10:1, preferably of 1:2 to 2:1.
 18. Apharmaceutical composition according to claim 1 in form of tablets,coated tablets, sachets and capsules.